Sjgren's syndrome is a chronic inflammatory, autoimmune disorder characterized clinically by dry mouth and dry eye (that is, keratoconjunctivitis sicca and xerostomia) as well as diminished lacrimal and salivary gland secretion. Patients with this condition routinely have lymphocytic infiltration of these exocrine glands. Systemic manifestations are common, including, but not limited to, inflammatory disease of the lungs, skin, CNS, PNS, kidneys as well as pathological levels of fatigue. Fatigue is a poorly treated facet of Sjgren's syndrome and some patients describe it as their most disabling symptom. Disease etiology is not well understood and treatment is mainly palliative. Free radical mediated damage, mitochondrial dysfunction and metabolic syndrome have been investigated only sporadically in Sjgren's syndrome and associations of these factors have not been studied. Studies of oxidative damage in Sjgren's syndrome are limited. We will study oxidative stress, metabolic syndrome and mitochondrial dysfunction and their inter-relationship in Sjgren's syndrome. Our preliminary data shows significantly increased oxidative damage as well as mitochondrial dysfunction in the disease. Metabolic syndrome is found in Sjgren's syndrome and is closely associated with chronic low level inflammation. But, the interaction and association of these three features of the illness are not known. Aim 1 of this project will determine oxidative damage and mitochondrial dysfunction in Sjgren's syndrome as well as the association between these conditions in the disease. We will use techniques for study of mitochondrial dysfunction and oxidative damage that can be applied to lymphocytes. Sjgren's presents an unusually scientific opportunity in that affected organs are routinely biopsied. So, we will study both peripheral blood lymphocytes as well as lymphocytes purified from minor salivary glands, a procedure with which we are highly familiar. Aim 2 will determine whether metabolic syndrome is correlated with either or both of mitochondrial dysfunction and free radical damage. These studies will take advantage of our large (n>400) cohort of well characterized Sjgren's patients. If there is correlation among oxidative damage, mitochondrial dysfunction and metabolic syndrome, then identifying a subgroup of Sjgren's syndrome patients with these characteristics may allow targeting of specific patients therapeutically. Rapamycin3 and N-acetylcysteine4 have efficacy in systemic lupus erythematosus (SLE). Both these molecules favorably affect mitochondrial dysfunction. N-acetylcysteine, which is FDA-approved, improved fatigue in SLE.4,5 Fatigue is a poorly treated facet of Sjgren's syndrome.